1. Field
The following description is related to a process for the preparation of a reaction intermediate of salmeterol, e.g., Compound 1, 2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol.
2. Background
Salmeterol is a long-acting β2-adrenergic receptor agonist drug that is prescribed for the treatment of asthma and chronic obstructive pulmonary disease (COPD). It is available as a dry powder inhaler that releases a powdered form of the drug.
The structure of salmeterol is illustrated as follows:

Salmeterol may be synthesized by reacting an intermediate a with an intermediate b. The intermediate a, intermediate b, and the synthesis route for the forgoing synthesis may be generally illustrated as follows:

However, this synthesis route leads to the generation of impurities D and G, the structure of each of which is illustrated below. These two impurities are difficult to remove, and therefore, the quality of the salmeterol product is affected by these impurities.

Salmeterol may also be synthesized by reacting intermediate Compound 1, e.g., 2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol with the long chain intermediate b or other similar compounds, while intermediate Compound 1 is protected utilizing the hydroxyl group. This process may reduce the production of impurities D and G.
The structure of Compound 1, e.g., 2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol, is illustrated below:

Compound 1, 2-Amino-1-(2,2-dimethyl-4H1,3-benzodioxin-6-yl)ethanol, may be synthesized utilizing dibenzylamine, sodium azide, and/or phenylglycinol as a nitrogen source (or aminating agent) and utilizing hydrogen as a source of hydrogenation for debenzylation and/or reduction. For example, Compound 1 may be synthesized as follows:
Compound 1 may be prepared utilizing dibenzylamine as the nitrogen source, followed by debenzylation by hydrogenation; utilizing sodium azide as the nitrogen source, followed by reduction by hydrogenation; utilizing nitromethane as the nitrogen source, followed by reduction by sodium borohydride; or utilizing phenylglycinol as the nitrogen source, followed by debenzylation by hydrogenation, etc. Such processes, however, are dangerous and difficult to industrialize.
Compound 1 may also be obtained through a five-step chemical reaction in which p-hydroxybenzaldehyde is utilized as the starting material and nitromethane is utilized as the nitrogen source. However, the stepwise percent yield for the reaction with nitromethane is only 62% (percent yield=actual yield÷theoretical yield×100) due to the weak nucleophilicity of nitromethane, which severely lowers the yield of the whole reaction.